Obesity is an increasingly important risk factor for cardiovascular disease in men and womenand is associated with the premature development of atherosclerosis, and increased risk of stroke. A classical perspective of cardiovascular risk does not adequately explain all of the cardiovascular events associated with obesity. Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are one of the biochemical hallmarks of obesity and likely contribute to the increased risk of atherothrombotic events in patients with obesity. For the last several years, this laboratory has been involved in a series of basic and clinical investigations that have helped to define the molecular physiology of PAI-1 and its role in the arterial thrombosis and arteriosclerosis. The central hypothesis of this proposal is that vascular PAI-1 excess promotes the development of intravascular thrombosis. In this proposal, we will test the hypothesis that secreted factors from adipocytes have autocrine, paracrine, and endocrine effects that have a deleterious effect on the fibrinolytic system, either by enhancing PAI-1 production or impairing endothelial t-PA release. This project will utilize genetic, proteomic, cellular, animal and human experimental systems to define the mechanisms of impaired fibrinolysis in obesity. From a public health perspective, there is no greater threat to America's cardiovascular health than the epidemic of obesity. It is anticipated that this study will provide new insights into the molecular mechanisms that contribute to the development of fibrinolytic dysfunction and cardiovascular disease in obesity.